After the MOL program was cancelled, Crippen became a NASA astronaut in September 1969. He served on the astronaut support crew for the Skylab 2, Skylab 3, and Skylab 4 missions, and for the Apollo-Soyuz Test Project mission. He was the Pilot of the first orbital test flight of the Space Shuttle program (STS-1, April 12–14, 1981) and was the Commander of three additional Shuttle flights: STS-7, June 18–24, 1983; STS-41-C, April 6–13, 1984; and STS-41-G, October 6–13, 1984. In addition to participating in the first Shuttle flight, he also presided over the first five-person crew (STS-7, which included Sally Ride, the first American woman in space), the first satellite repair operation (STS-41-C, which repaired the Solar Maximum Mission satellite), and the first seven-person crew (STS-41-G). He was named Commander of the STS-62-A mission which would have launched from the new SLC-6 facility at Vandenberg Air Force Base, California. That mission was cancelled after the Space Shuttle Challenger disaster and SLC-6 was closed when the Air Force went back to launching satellites on the Titan III and Titan IV rockets.

Crippen was stationed at Kennedy Space Center, Florida, from July 1987 to December 1989, as Deputy Director, Shuttle Operations for NASA Headquarters. He was responsible for final Shuttle preparation, mission execution and return of the orbiter to KSC after landings at Edwards Air Force Base. From January 1990 to January 1992, he served as Director, Space Shuttle, at NASA Headquarters in Washington, D.C. As such, he was responsible for the overall Shuttle program requirements, performance, and total program control, including budget, schedule and program content. He subsequently served as the Director of the Kennedy Space Center from January 1992 to January 1995. During his tenure, the center processed, safely launched, and recovered 22 Space Shuttle missions. He led more than 13,000 civil service and contractor personnel. This included oversight of multiple contracts supporting center operations for manned and unmanned spaceflight. He also cut costs more than 25% with quality management techniques.[citation needed]

STS-1: Columbia (April 12–14, 1981) was the first orbital test flight of the Space Shuttle Columbia, the first true manned spaceship. It was also the first manned vehicle to be flown into orbit without benefit of previous unmanned "orbital" testing; the first to launch with wings using solid rocket boosters. It was also the first winged reentry vehicle to return to a conventional runway landing, weighing more than 99-tons as it was braked to a stop on the dry lakebed at Edwards Air Force Base, California. Mission duration was 54 hours, 20 minutes, 53 seconds.

STS-7: Challenger (June 18–24, 1983) was the second flight for the Orbiter Challenger. This was also the first mission with a 5-person crew. During the 6-day flight the crew deployed satellites for Canada (ANIK C-2) and Indonesia (PALAPA B-1); operated the Canadian-built Remote Manipulator System (RMS) to perform the first deployment and retrieval exercise with the Shuttle Pallet Satellite (SPAS-01); conducted the first formation flying of the orbiter with a free-flying satellite (SPAS-02); carried and operated the first U.S./German cooperative materials science payload (OSTA-2); and operated the Continuous Flow Electrophoresis System (CFES) and the Monodisperse Latex Reactor (MLR) experiments, in addition to activating seven Getaway Specials. Mission duration was 146 hours, 23 minutes, 59 seconds.

STS-41-C: Challenger (April 6–13, 1984) was a 7-day mission during which the crew successfully deployed the Long Duration Exposure Facility (LDEF); retrieved the ailing Solar Maximum Satellite, repaired it on-board the orbiting Challenger, and replaced it in orbit using the robot arm called the Remote Manipulator System (RMS); flight tested the Manned Maneuvering Units (MMU's) in two extravehicular activities (EVA); as well as operating the Cinema 360 and IMAX Camera Systems, and a Bee Hive Honeycomb Structures student experiment. Mission duration was 167 hours, 40 minutes, 07 seconds.

STS-41-G: Challenger (October 5–13, 1984) was the first mission with a 7-person crew. During the 8-day flight the crew deployed the Earth Radiation Budget Satellite, conducted scientific observations of the Earth with the OSTA-3 pallet and Large Format Camera, as well as demonstrating potential satellite refueling with an EVA and associated hydrazine transfer. Mission duration was 197 hours, 23 minutes, 37 seconds and concluded with a landing at Kennedy Space Center, Florida.

Crippen's first marriage produced three daughters: Ellen Marie (born June 14, 1962), Susan Lynn (born December 24, 1964), and Linda Ruth (born May 10, 1967). His second marriage is to Pandora Lee Puckett of Miami, Florida, NASA’s first female lead Orbiter Project Engineer on the Space ShuttleAtlantis and Challenger at the Kennedy Space Center.